Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.277 g, 1.07 mmol), hydrazine monohydrate (0.5 mL) and DMSO (2.0 mL) were stirred at room temperature overnight. Then the reaction was heated to 50° C. and stirred for 7 hours. Purified by RP-HPLC to provide 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as an orange solid (0.118 g, 43%). LCMS: (M+H)+=255.3.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13].C([BH3-])#N.[Na+]>O>[C:6]([CH:5]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13])[CH2:4][CH:3]([CH3:10])[CH3:2])([OH:8])=[O:7]
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CC(C)CC(N[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
A solution of the sodium salt of 4-methyl-2-oxopentanoic acid (414 mg) and L-alanyl-L-tryptophan (150 mg) in water are adjusted to pH 7 with caustic and treated with sodium cyanoborohydride (103 mg) at room temperature for several days. The product is absorbed on strong acid ion exchange resin and eluted with 2% pyridine in water. The product rich cuts are freeze dried affording 189 mg of fluffly white solid. The mass spectrum shows a molecular ion at 389 m/e and peaks at 187 m/e and 158 m/e for the fragments shown respectively: ##STR15## The nmr spectrum in D2O is consistent with structure.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].[OH-].[Li+].C(O)C.O>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of carbamate (Example 7; 360 mg 0.00094 mol, cis and trans mixture) and lithium hydroxide (248 mg, 0.0104 mol) in ethanol (6.0 mL, 0.10 mol) and water (2.0 mL, 0.11 mol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product (220 mg, 66%). Separation on ChiralPak-ADH (5μ, 4.6 mm×250 mm, 2 mL/min, 25% (0.3% DEA in MeOH) in CO2, 100 bar, 36° C.) gave peak 1, Rf=8.373 min, 87 mg (87.9% yield, 96.4% ee), and peak 2, Rf=12.479 min, 74 mg (74.7% yield, 97.0% ee). Peak 1 was purified on Si gel (0-100% MeOH/DCM) to give 26.2 mg; peak 2 was purified on Si gel (0-100% MeOH/DCM) to give 44.3 mg. LCMS 339.71 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.93 (t, J=6.9 Hz, 3H), 1.14 (ddd, J=14.7, 13.4, 3.0 Hz, 2H), 1.24-1.39 (m, 7H), 1.45 (ddd, J=14.7, 12.5, 3.3 Hz, 2H), 1.56 (s, 3H), 1.89 (br d, J=13.0 Hz, 2H), 2.22 (brd, J=12.5 Hz, 2 H), 3.70 (d, J=10.9 Hz, 1H), 3.76 (d, J=10.9 Hz, 1H), 4.37 (m, 1H), 7.11 (dd, J=9.0, 2.6 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.55 (dd, J=8.7, 2.0 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.76 (d, J=6.9 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)cc(CCC(=O)O)n4C)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
Sodium hydroxide (57 mg) was added to a solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (E113) (67 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoic acid (E88) (1 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.71 (2H, t), 3.02 (2H, t), 3.75 (3H, s), 4.88 (1H, m), 6.40 (1H, s), 7.44 (1H, d), 7.59 (1H, d), 7.81 (1H, dd), 8.11 (1H, dd), 8.18 (1H, d), 8.24 (1H, d), 12.33 (1H, br); MS (ES): C23H22ClN3O4 requires 439; found 440.2 (M+H+).
Reaction SMILES: [ClH:1].O1CCOCC1.C(O)(C(F)(F)F)=O.[CH3:15][O:16][C:17]([NH:19][C@@H:20]([CH:68]([CH3:70])[CH3:69])[C:21]([N:23]1[C@H:28]([C:29]2[NH:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[CH:46]=[C:45]([C:50]4[NH:54][C:53]([C@@H:55]6[CH2:60][C@@H:59]7[C@@H:57]([CH2:58]7)[N:56]6C(OC(C)(C)C)=O)=[N:52][CH:51]=4)[CH:44]=[CH:43]5)=[CH:36][CH:35]=3)=[CH:32][N:33]=2)[CH2:27][C@@H:26]2[C@H:24]1[CH2:25]2)=[O:22])=[O:18]>C(Cl)Cl>[ClH:1].[ClH:1].[C@@H:57]12[CH2:58][C@@H:59]1[CH2:60][C@@H:55]([C:53]1[NH:54][C:50]([C:45]3[CH:46]=[C:47]4[C:42](=[CH:43][CH:44]=3)[CH:41]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]5[NH:30][C:29]([C@@H:28]6[CH2:27][C@@H:26]7[C@@H:24]([CH2:25]7)[N:23]6[C:21](=[O:22])[C@@H:20]([NH:19][C:17](=[O:18])[O:16][CH3:15])[CH:68]([CH3:70])[CH3:69])=[N:33][CH:32]=5)=[CH:35][CH:36]=3)[CH:49]=[CH:48]4)=[CH:51][N:52]=1)[NH:56]2
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl in dioxane (2 mL, 8.00 mmol) was added to a stirred solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-(6-(4-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.10 g, 0.12 mmol) in CH2Cl2 (20 mL) and the resulting yellow suspension was stirred at rt for 2 h. The reaction was concentrated under vacuum and the resulting residue was triturated with Et2O to yield an HCl salt of methyl(S)-1-((1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate HCl (47 mg) as a yellow solid. LC/MS [M+H]+=656; Rt=1.73 min is product. Column Luna 3u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10% Acetonitrile/90% H2O+1% TFA; Solvent B: 90% Acetonitrile/10% H2O+1% TFA; flow rate 4 ml/min. Run time: 5 min. Purity=95%. 1H NMR (500 MHz, DMSO-d6) δ ppm 14.47-15.18 (2 H, m), 9.77-10.61 (2 H, m), 8.30-8.42 (2 H, m), 8.17 (1 H, s), 7.93-8.10 (10 H, m), 7.27 (1 H, d, J=8.55 Hz), 5.08 (1 H, t, J=7.93 Hz), 4.71 (1 H, t, J=8.39 Hz), 4.40-4.46 (1 H, m), 3.77 (1 H, br. s.), 3.52-3.58 (3 H, m), 3.38-3.44 (1 H, m), 2.52-2.61 (3 H, m), 2.39 (1 H, dt, J=13.58, 6.64 Hz), 2.14-2.21 (1 H, m), 1.94 (2 H, dd, J=8.24, 4.88 Hz), 1.15 (1 H, d, J=5.80 Hz), 0.93 (4 H, d, J=6.71 Hz), 0.75-0.89 (6 H, m).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21]C)[CH:5]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:11][C:12]3[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([OH:21])=[CH:7][C:8]=3[CH:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)C)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 1 h
Yield: 338.8 %

Procedure:
7-Isopropyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran 117 (0.26 g, 0.88 mmol) and Pyridine HCl (5 g) wre heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and the product was purified by column chromatography on silica gel (25% EtOAc/hexane) to give 118 as a solid (0.80 g, 34%): Mp=192-194° C.; 1H NMR (DMSO-d6) δ 9.81 (br s, 1 H), 9.03 (br s, 1 H), 7.68 (d, 2 H, J=8.2 Hz), 6.98 (s, 1 H), 6.86 (d, 2H, J=8.1 Hz), 6.69 (d, 1 H, J=1.4 Hz), 6.54 (d, 1 H, J=1.9 Hz), 3.31 (m, 1 H), 1.32 (d, 6 H, J=6.9 Hz); MS 269 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy) benzyl]-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (1.1 mmoles, 0.40 g) and THF (7 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164-165° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[CH:18]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cn(Cc2ccc(C#N)cc2)nn1

Procedure:
38.9 g of 4-azidomethylbenzonitrile is refluxed in 400 ml of toluene with 42 ml of trimethylsilylacetylene for 5 hours at 120°, combined with another 21 ml of trimethylsilylacetylene, and once again refluxed for 3 hours at 120°. Then the mixture is concentrated under vacuum, yielding 63 g of crude 4-[4-trimethylsilyl-(1,2,3-triazol-1-yl)methyl]benzonitrile. The latter is refluxed with a mixture of 700 ml of glacial acetic acid, 380 ml of water, as well as 110 ml of tetrahydrofuran for 2 hours. For working up purposes, the mixture is poured into sodium bicarbonate solution, extracted three times with dichloromethane, washed neutral with water, dried over sodium sulfate, concentrated to dryness under vacuum, and recrystallized from ethyl acetate/hexane, yielding 32.8 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile as colorless crystals, mp 83°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride (0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from ethyl acetate to yield 0.17 g (43%) of the title compound as a white solid mp 174°-175° C. HRMS m/e calculated for C22H22ClN3O: 379.1448. Observed m/e: 379.1465. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([N:23]([CH3:29])[C@H:24]([C:26]([OH:28])=O)[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl.C[O:32][C:33](=[O:44])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[NH2:35]>C(OCC)(=O)C>[N:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:29])[C@H:24]([C:26]([NH:35][C@H:34]([C:33]([OH:44])=[O:32])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)=[O:28])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
1 liter of ethyl acetate under nitrogen is cooled to between -5° and 0° C. and isobutyl chloroformate (37.6 ml, 290 mmole) is added followed by N-methylmorpholine (31.9 ml, 290 mmole). A sticky white solid forms and after 10 minutes BOC-N-methylalanine (58.9 grams, 290 mmoles) is added. A more granular solid forms and after 20 minutes tyrosine methylesterhydrochloride (57.93 grams, 250 mmoles) is added. Additional N-methylmorpholine (27.9 ml, 250 mmoles) is then added to obtain a pH of about 8. After 2.5 hours of stirring the mixture is washed three times with 500 ml of 1 N sodium bicarbonate and three times with 500 ml of 0.5 molar citric acid and dried over sodium sulfate. The reaction mixture is concentrated in vacuo affording the following crops of crystalline materials:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10]2)=[CH:5][CH:4]=1.C(N([CH2:25][CH3:26])CC)C.[CH2:27]([O:31][C:32](Cl)=[O:33])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:27]([O:31][C:32]([N:12]1[CH2:13][C@H:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:10][C@H:11]1[CH2:14][CH2:15][CH2:16][O:17][C:32]([O:31][CH2:27][CH2:28][CH2:25][CH3:26])=[O:33])=[O:33])[CH2:28][CH2:29][CH3:30].[CH2:27]([O:31][C:32]([N:12]1[CH2:13][C@H:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:10][C@H:11]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOC(=O)Cl
Reactant: COc1ccc(CS[C@H]2CN[C@H](CCCO)C2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1C[C@H](SCc2ccc(OC)cc2)C[C@H]1CCCO
Product: CCCCOC(=O)OCCC[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OCCCC
Yield: 32 %
Yield: 28 %

Procedure:
A solution of 615 mg (2.19 mmol) (2R,4R)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-ol and 0.34 ml (2.40 mmol) triethylamine in 5 ml CH2Cl2 was cooled to −10° C. and treated slowly with 0.31 ml (2.29 mmol) butylchloroformate. After 20 min at this temperature the reaction was extracted with cold (0° C.) aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous saturated NaHCO3 dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with hexane/EtOAc (2:1 to 1:1) gave 340 mg (32%) of (2R,4R)-2-(3-butoxycarbonyloxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester and 230 mg (28%) of (2R,4R)-2-(3-hydroxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester, MS: 382 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:14]=[N:13]2)[C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:14]=[N:13]3)[C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc(C)c(C)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 8 was prepared by coupling 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 549 [C28H32N6O4S+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1)=[O:4].[C:30](Cl)(Cl)=[O:31].C(N(CC)CC)C.O>ClCCCl>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[C:10]2[CH:27]=[C:6]([N:5]3[C:3](=[O:4])[C:2]([CH3:29])([CH3:28])[NH:1][C:30]3=[O:31])[CH:7]=[CH:8][C:9]=2[N:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[N:12]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)C(C)(C)N)ccc21
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N3C(=O)NC(C)(C)C3=O)ccc21

Procedure:
2 g (0.005 mol) of 2 amino-N-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-2-methylpropionamide are dissolved in 50 ml of 1,2-dichloroethane and added to 1 g of phosgene in 50 ml of 1,2-dichloroethane at room temperature. The reaction mixture is stirred for 1/2 hour and subsequently made basic with triethylamine. The mixture is treated with water and extracted with methylene chloride. The organic phase is dried and evaporated. The residue gives, from ethyl acetate/ether, 3-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-5,5-dimethylhydantoin of melting point 286°-287°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[S:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH2:14][S:10][CH2:11]2)=[CH:4][N:3]=1
Reactant: C1CSCN1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCSC2)cn1
Temperature: 80 °C
Yield: 41.6 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 4 mL of dry acetonitrile is added 0.42 mL (6.17 mmol) of thiazolidine followed by 852 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 275 mg (42% yield) of 2-Chloro-5-thiazolidin-3-ylmethyl-pyridine. Diagnostic C13 NMR (100 MHz, CDCl3) 29.8, 53.6, 57.7, 60.3, 112.4, 124.4, 133.3, 139.6, 150.1; MS 215.2 (M+H).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.Cl.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[CH2:59][NH2:60]>>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[CH2:59][NH:60][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2[nH]1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2[nH]1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride, the title compound was obtained as a colorless solid in 80% yield: mp 265-267° C.: 1H NMR (300 MHz, DMSO-d6) δ 12.19 (br s, 1H), 8.23 (t, J=5.5 Hz, 1H), 7.54-7.46 (m, 2H), 7.38-7.31 (m, 2H), 7.24-7.10 (m, 4H), 6.25 (s, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.39 (s, 2H), 3.87-3.78 (m, 2H), 3.48-3.39 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 159.9, 155.5, 152.5, 142.9, 139.2, 132.9 (d, JC-F=3.0 Hz), 129.9 (d, JC-F=8.2 Hz), 121.3, 120.0, 115.3 (d, JC-F=21.2 Hz), 112.1, 46.3, 42.5, 41.3, 37.7, 15.8; MS (ES+) m/z 464.4 (M+1).
Reaction SMILES: COC1C=CC(CN(C)[N:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=O)[CH2:23]4)=[CH:18][CH:17]=3)=[CH:11][CH2:10]2)=CC=1.[C:32]([C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39])([CH3:35])([CH3:34])[CH3:33].CCN=C=N[CH2:48][CH2:49][CH2:50][N:51]([CH3:53])C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:32]([C:36]1[CH:37]=[C:38]([NH:39][C:26]([CH:22]2[CH2:21][CH2:20][C:19]3[C:24](=[CH:25][C:16]([O:15][C:12]4[CH:11]=[CH:10][N:9]=[C:14]([N:51]([CH2:50][C:49]5[CH:48]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=5)[CH3:53])[CH:13]=4)=[CH:17][CH:18]=3)[CH2:23]2)=[O:28])[CH:40]=[CH:41][CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: COc1ccc(CN(C)N2C=CC(Oc3ccc4c(c3)CC(C(=O)O)CC4)=CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(C)c2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)cc1
Reaction time: 18 h

Procedure:
To a solution of 7-({1-[(4-methoxybenzyl)(methyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (581 mg, 1.39 mmol) and 3-tert-butylaniline (228 mg, 1.53 mmol) in DCM (13 mL), was added DMAP (186 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol). The reaction mixture was allowed to stir for 18 hr, and then diluted with EtOAc and washed with water and brine. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by column to give N-(3-tert-butylphenyl)-7-({2-[(4-methoxybenzyl)(methyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (I-179) as a white solid (491 mg, 64.3%). 1H NMR (400 MHz, d6-DMSO; HCl salt) δ: 9.98 (s, 1H), 7.97 (d, 1H), 7.64 (dd, 1H), 7.49 (d, 1H), 7.21 (dd, 1H), 7.20 (d, 1H), 7.12 (d, 2H), 7.07 (ddd, 1H), 6.96 (d, 1H), 6.87-6.92 (m, 3H), 6.37-6.49 (m, 2H), 4.69 (s, 2H), 3.72 (s, 3H), 3.17 (s, 3H), 2.72-2.99 (m, 5H), 2.03-2.99 (m, 1H), 1.73-1.84 (m, 1H), and 1.26 (s, 9H). LCMS: (FA) ES+ 550.3, ES− 448.4.